Mutant desmocollin-2 causes arrhythmogenic right ventricular cardiomyopathy


  • A. Heuser
  • E.R. Plovie
  • P.T. Ellinor
  • K.S. Grossmann
  • J.T. Shin
  • T. Wichter
  • C.T. Basson
  • B.B. Lerman
  • S. Sasse-Klaassen
  • L. Thierfelder
  • C.A. MacRae
  • B. Gerull


  • American Journal of Human Genetics


  • Am J Hum Genet 79 (6): 1081-1088


  • Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetically heterogeneous heart-muscle disorder characterized by progressive fibrofatty replacement of right ventricular myocardium and an increased risk of sudden cardiac death. Mutations in desmosomal proteins that cause ARVC have been previously described; therefore, we investigated 88 unrelated patients with the disorder for mutations in human desmosomal cadherin desmocollin-2 (DSC2). We identified a heterozygous splice-acceptor–site mutation in intron 5 (c.631-2A->G) of the DSC2 gene, which led to the use of a cryptic splice-acceptor site and the creation of a downstream premature termination codon. Quantitative analysis of cardiac DSC2 expression in patient specimens revealed a marked reduction in the abundance of the mutant transcript. Morpholino knockdown in zebrafish embryos revealed a requirement for dsc2 in the establishment of the normal myocardial structure and function, with reduced desmosomal plaque area, loss of the desmosome extracellular electron-dense midlines, and associated myocardial contractility defects. These data identify DSC2 mutations as a cause of ARVC in humans and demonstrate that physiologic levels of DSC2 are crucial for normal cardiac desmosome formation, early cardiac morphogenesis, and cardiac function.